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The

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Original Article

Pioglitazone after Ischemic Stroke


or Transient Ischemic Attack
W.N. Kernan, C.M. Viscoli, K.L. Furie, L.H. Young, S.E. Inzucchi, M. Gorman,
P.D. Guarino, A.M. Lovejoy, P.N. Peduzzi, R. Conwit, L.M. Brass,* G.G. Schwartz,
H.P. Adams, Jr., L. Berger, A. Carolei, W. Clark, B. Coull, G.A. Ford, D. Kleindorfer,
J.R. OLeary, M.W. Parsons, P. Ringleb, S. Sen, J.D. Spence, D. Tanne, D. Wang,
and T.R. Winder, for the IRIS Trial Investigators

A BS T R AC T
BACKGROUND

Patients with ischemic stroke or transient ischemic attack (TIA) are at increased
risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction
raised the possibility that pioglitazone, which improves insulin sensitivity, might
benefit patients with cerebrovascular disease.

The authors full names, academic degrees, and affiliations are listed in the
Appendix. Address reprint requests to Dr.
Kernan at 2 Church St. S., Suite 515, New
Haven, CT 06519, or at walter.kernan@
yale.edu.
*Deceased.

METHODS

In this multicenter, double-blind trial, we randomly assigned 3876 patients who


had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose,
45 mg daily) or placebo. Eligible patients did not have diabetes but were found to
have insulin resistance on the basis of a score of more than 3.0 on the homeostasis
model assessment of insulin resistance (HOMA-IR) index. The primary outcome
was fatal or nonfatal stroke or myocardial infarction.

A complete list of the Insulin Resistance


Intervention after Stroke (IRIS) trial investigators is provided in the Supplementary Appendix, available at NEJM.org.

RESULTS

Copyright 2016 Massachusetts Medical Society.

This article was published on February 17,


2016, at NEJM.org.
N Engl J Med 2016;374:1321-31.
DOI: 10.1056/NEJMoa1506930

By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in
the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard
ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93;
P=0.007).Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95%
CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of
weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema
(35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization
(5.1% vs. 3.2%, P=0.003).
CONCLUSIONS

In this trial involving patients without diabetes who had insulin resistance along
with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial
infarction was lower among patients who received pioglitazone than among those
who received placebo. Pioglitazone was also associated with a lower risk of diabetes
but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number,
NCT00091949.)

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schemic stroke and transient ische


mic attack (TIA) affect more than 14 million
persons worldwide annually.1,2 Affected patients are at increased risk for future cardiovascular events,3,4 and prevention of these adverse
outcomes is a major goal in their care.
Treatment of insulin resistance represents a
potential new preventive strategy that could be
added to standard care after ischemic stroke or
TIA.5 Insulin resistance is nearly universal in
patients with type 2 diabetes but is also present
in more than 50% of patients without diabetes
who have had an ischemic stroke or a TIA.6 The
presence of insulin resistance increases the risk
of vascular disease, possibly because of associated hypertension, hyperglycemia, hyperinsulinemia, dyslipidemia, endothelial dysfunction,
hypercoagulability, inflammation, and increased
platelet reactivity.7-9
Clinical strategies to improve insulin sensitivity
include exercise,9,10 diet,11 weight reduction,12 and
medications.9,13 The thiazolidinedione class of per
oxisome proliferatoractivated receptor (PPAR-)
agonists are among the most potent insulinsensitizing drugs available.14 One medication in
this class, pioglitazone, may reduce the risk of
cardiovascular events, including stroke, in patients with type 2 diabetes, for whom the drug is
currently approved as a glucose-lowering agent.15,16
We designed the Insulin Resistance Intervention
after Stroke (IRIS) trial to test the hypothesis
that pioglitazone would reduce the rates of
stroke and myocardial infarction after ischemic
stroke or TIA in patients without diabetes who
have insulin resistance.

Me thods
Trial Design and Oversight

The design of this international, double-blind,


placebo-controlled clinical trial has been reported
previously.17 Trial leadership, committee structure, and sites are described in the Supplementary Appendix, available with the full text of this
article at NEJM.org. Members of the operations
committee and the statisticians designed the
study. From 2005 through 2013, investigators at
179 hospitals and clinics enrolled patients and
collected data. The statistical analysis was performed at the Department of Veterans Affairs
Connecticut Health Care System. The first author
wrote the first draft of the manuscript. All the
other authors contributed revisions and vouch
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for the reported data. Pioglitazone and placebo


tablets were donated by Takeda Pharmaceuticals
International. Representatives of Takeda were
provided with a copy of the protocol (available at
NEJM.org) and manuscript but had no role in the
development of the protocol, the conduct of the
trial, the interpretation of the data, or the preparation of the manuscript. The trial was monitored
by an independent data and safety monitoring
board appointed by the National Institute of Neurological Disorders and Stroke, which funded the
study. Trial operations were approved by the local
ethics committee at each site. The study was conducted and reported with fidelity to the protocol.
Trial Patients

Eligible patients were at least 40 years of age and


had had a qualifying ischemic stroke or TIA17
during the 6 months before randomization. All
the patients provided written informed consent.
Patients were required to have insulin resistance,
which was defined as a value of more than 3.0
on the homeostasis model assessment of insulin
resistance (HOMA-IR) index. The HOMA-IR value
was calculated as the level of fasting glucose
(measured in millimoles per liter) times the
level of fasting insulin (measured in microunits
per milliliter) divided by 22.5.18 The index threshold of 3.0 was chosen because it identifies the
highest quartile among populations without diabetes.19,20 Because insulin sensitivity may be transiently impaired after a stroke,21 the screening
blood test was conducted at least 14 days after
the index event.
Patients with diabetes were excluded from the
trial. Diabetes was diagnosed if a potential participant was taking medication for diabetes or
met the 2005 criteria of the American Diabetes
Association (ADA) for fasting plasma glucose
(i.e., 126 mg per deciliter [7 mmol per liter]),
as confirmed by repeated testing.22 We did not
perform an oral glucose-tolerance test but excluded patients with a glycated hemoglobin level
of 7.0% or more. We also excluded patients with
New York Heart Association class 3 or 4 heart
failure or class 2 heart failure with a reduced
ejection fraction.17 Other criteria for exclusion
included active liver disease, an alanine aminotransferase level of more than 2.5 times the upper limit of the normal range, a hemoglobin
level of less than 8.5 g per deciliter, moderate or
severe dependent pitting edema, carotid revascularization within 14 days before randomization,

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Pioglitazone after Ischemic Stroke or TIA

and use of an estrogen-containing contraceptive


or oral glucocorticoid. In response to regulatory
changes that were adopted during the trial, the
data and safety monitoring board approved additional exclusions for a history of heart failure,
bladder cancer, or certain conditions that increased the risk of bladder cancer.17

baseline, as assessed by means of the Modified


MiniMental State Examination (on which scores
range from 0 to 100, with higher scores indicating better function23).17 No other outcomes were
prespecified. All outcomes and selected safety
events (i.e., bone fracture, macular edema, and
cancer) were adjudicated by the members of independent committees in a blinded fashion.

Trial Procedures

Eligible patients were randomly assigned in a 1:1


ratio to receive either pioglitazone or matching
placebo. The initial dose was 15 mg of pioglita
zone daily or placebo. Patients who reported no
new or worsening edema, shortness of breath,
myalgia, or excessive weight gain were instructed
to increase the dose to two pills daily (30 mg of
pioglitazone or placebo) at 4 weeks and to three
pills daily (45 mg of pioglitazone or placebo) at
8 weeks. At 12 weeks, patients were started on
one 45-mg pioglitazone tablet or placebo tablet
daily.
If patients reported any of the aforementioned
signs or symptoms, study investigators treated
them according to algorithms. A reduction in
study-drug dose was included in the algorithms
and was also permitted by the internal safety
committee if such a reduction allowed the patient to continue taking the drug. Pioglitazone
and placebo were permanently discontinued if
heart failure or bladder cancer developed or if a
patient had two distinct low-energy bone fractures (i.e., resulting from a fall from a sitting or
standing position or from a low platform, such
as a bed).
Patients were contacted every 4 months, and
participation ended at 5 years or at the last
scheduled contact before July 2015. Investigators
monitored patients adherence to the assigned
regimen by asking about drug use and performing pill counts. If a patient briefly stopped taking
a study drug, investigators included such intervals as zero use in calculations of adherence.
Adherence calculations were stopped at the date
a patient withdrew consent.
Trial Outcomes

The primary outcome was a first fatal or nonfatal stroke or fatal or nonfatal myocardial infarction.17 Prespecified secondary outcomes were
stroke; acute coronary syndrome; the composite
of stroke, myocardial infarction, or heart failure
resulting in hospitalization or death; death from
any cause; diabetes; and cognitive decline from

Statistical Analysis

We determined that enrollment of 3136 patients


would provide a power of 90% to detect a 4-year
cumulative rate of stroke or myocardial infarction that was 20% lower in the pioglitazone
group than in the placebo group, assuming a
two-sided type I error of 0.05 and a 27% outcome rate in the placebo group. Four interim
analyses of the primary outcome were conducted
for efficacy and futility with the use of the
OBrienFleming method.19 At the second and
third interim analyses, the data and safety
monitoring board recommended an extension of
recruitment and follow-up owing to slower recruitment and a lower overall event rate than
anticipated in order to maintain the statistical
power. Decisions were made in closed sessions,
and investigators were not aware of event rates
during the trial.
All analyses were performed on an intentionto-treat basis. The primary outcome and all
prespecified secondary outcomes except cognitive
function were analyzed by means of the time-tofirst-event method. Cumulative event-free probabilities were calculated with the use of Kaplan
Meier analysis24 and tested with the use of the
log-rank statistic on the basis of a two-sided
type I error rate of 0.05. The P value for the primary outcome was adjusted for interim monitoring with the use of East software, version 6.3
(Cytel), and the P values for the five prespecified
time-to-event secondary outcomes were adjusted
for multiple testing with the Hochberg procedure and a family-wise error rate of 0.05. We used
the Cox model25 to estimate the effect of pioglitazone, as compared with placebo, as a hazard
ratio with 95% confidence intervals. The confidence interval for the primary outcome was adjusted for interim analyses with the use of East
software, version 6.3, and confidence intervals
for the secondary outcomes were adjusted for
multiple comparisons with the method of Efird
and Nielsen.26 In planned supplementary analyses,
the Cox model was used to estimate the hazard

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ratio for the primary outcome after adjustment


for prespecified baseline covariates and to test for
interactions between treatment and covariates in
13 prespecified subgroups, with P values adjusted
for multiple testing.27 Missing time-to-event data
were treated as noninformative censoring. We
used a repeated-measures covariance-pattern
model on the assumption that data were missing
at random to analyze the effect of treatment on
cognitive function; in this analysis, the change
from baseline in the annual score on the Modified
MiniMental State Examination was the outcome.
We also conducted two types of ancillary
analysis. During the trial, new definitions for
stroke,28 myocardial infarction,29 and diabetes30
were published. The data and safety monitoring
board approved ancillary analyses that used these
updated outcome definitions. In addition, we
examined changes in measures reported to be affected by pioglitazone, including the HOMA-IR
index; insulin, glucose, lipid, and C-reactive protein levels; and blood pressure. All these measures were listed in the protocol but were not
considered to be outcome events. P values for
safety and ancillary analyses were not adjusted
for multiple comparisons. We used SAS software,
version 9.3, for all analyses, except as noted.

the ADA (which include a glycated hemoglobin


level of 6.5% as diagnostic of diabetes), diabetes was present in 116 of 1939 patients (6.0%) in
the pioglitazone group and in 129 of 1937 (6.7%)
in the placebo group (Table S2 in the Supplementary Appendix).
During a median follow-up of 4.8 years, a
total of 227 patients (5.9%) withdrew consent
and 99 (2.6%) were lost-to-follow-up (Fig. S1 in
the Supplementary Appendix). Baseline features
were similar for patients who were lost to followup in the two groups. Patients in the two groups
had similar rates of adherence to recommended
practices for secondary prevention (Table S3 in
the Supplementary Appendix).
Patients in the pioglitazone group had lower
adherence to the drug regimen than did those in
the placebo group (Table S4 in the Supplementary Appendix); at the exit visit, 60% of the patients in the pioglitazone group were still taking
pioglitazone and 67% in the placebo group were
still taking placebo. The reasons for drug discontinuation were similar in the two groups, except that more patients in the pioglitazone group
than in the placebo group stopped because of
edema or weight gain (172 patients vs. 51 patients)
or were removed for safety reasons (primarily
heart failure, repeated fracture, and incidence of
or risk factors for bladder cancer) (146 patients
R e sult s
vs. 117 patients). In the pioglitazone group, the
Trial Population
median daily dose each year ranged from 29 mg
A total of 3895 patients were enrolled, with 67% to 40 mg.
from sites in the United States (Fig. S1 in the
Supplementary Appendix). Alleged irregularity in Clinical Outcomes
the informed-consent process at one institution The primary outcome of stroke or myocardial
resulted in halting of local research activities infarction occurred in 175 of 1939 patients (9.0%)
while the data were still blinded. The 19 patients in the pioglitazone group and in 228 of 1937
at this site were removed from the study, result- (11.8%) in the placebo group (hazard ratio in the
ing in a final cohort of 3876 patients (1939 in pioglitazone group, 0.76; 95% confidence interval
the pioglitazone group and 1937 in the placebo [CI], 0.62 to 0.93; P=0.007) (Table2 and Fig. 1,
group).
and Table S5 in the Supplementary Appendix).
The two study groups had similar character- This finding did not change after adjustment for
istics at baseline (Table1, and Table S1 in the covariates.
Supplementary Appendix). In the two study
Among the secondary outcomes, the rate of
groups, the mean age was 63.5 years. The index progression to diabetes was significantly lower
event was stroke in 88% of the patients in the in the pioglitazone group than in the placebo
pioglitazone group and 87% in the placebo group (hazard ratio, 0.48; 95% CI, 0.33 to 0.69;
group; the median times from the index event to P<0.001) (Table2). Pioglitazone had no signifirandomization were 81 days and 79 days, respec- cant effect on cognition, as compared with platively, and the median HOMA-IR index values cebo. The overall between-group difference in
were 4.7 and 4.6, respectively. In the two study the change from baseline in the least-squares
groups, the mean baseline glycated hemoglobin mean score on the Modified MiniMental State
level was 5.8%. According to the 2010 criteria of Examination was 0.02 (95% CI, 0.33 to 0.28;

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Pioglitazone after Ischemic Stroke or TIA

Table 1. Characteristics of the Patients at Baseline.*


Pioglitazone
(N=1939)

Characteristic

Placebo
(N=1937)

Demographic feature
Age yr

63.510.6

63.510.7

1293 (66.7)

1245 (64.3)

218/1906 (11.4)

225/1904 (11.8)

75/1927 (3.9)

72/1929 (3.7)

At entry

1693/1928 (87.8)

1682/1930 (87.2)

Previous

246/1938 (12.7)

242/1935 (12.5)

Hypertension no./total no. (%)

1380/1938 (71.2)

1390/1936 (71.8)

Coronary artery disease no./total no. (%)

241/1938 (12.4)

221/1936 (11.4)

134/1914 (7.0)

130/1912 (6.8)

29.95.6

30.05.3

Male sex no. (%)


Black race no./total no. (%)
Hispanic ethnic group no./total no. (%)
Clinical history
Stroke no./total no. (%)

Atrial fibrillation no./total no. (%)


Physical and cognitive examination
Body-mass index
Blood pressure mm Hg
Systolic

133.217.7

133.017.3

Diastolic

79.410.7

79.010.5

96 (9299)

97 (9299)

Score on Modified MiniMental State Examination median (IQR)


Score on NIH Stroke Scale median (IQR)

0 (02)

0 (01)

Score on Modified Rankin Scale median (IQR)

1 (02)

1 (01)

Laboratory data
Fasting glucose mg/dl

98.310.0

98.29.9

Median fasting insulin (IQR) U per milliliter

19 (1626)

19 (1625)

HOMA-IR index median (IQR)

4.7 (3.86.2)

4.6 (3.76.2)

5.80.4

5.80.4

LDL

87.631.5

87.931.5

HDL

47.012.8

47.112.6

142.573.8

139.471.8

Statin no./total no. (%)

1594/1932 (82.5)

1592/1932 (82.4)

Antiplatelet no./total no. (%)

1781/1936 (92.0)

1786/1934 (92.3)

Oral anticoagulant no./total no. (%)

232/1932 (12.0)

209/1932 (10.8)

ACE inhibitor or angiotensin-receptor blocker no./total no. (%)

1090/1932 (56.4)

1054/1932 (54.6)

Diuretic no./total no. (%)

581/1932 (30.1)

534/1932 (27.6)

Beta-blocker no./total no. (%)

615/1932 (31.8)

613/1932 (31.7)

Glycated hemoglobin %
Fasting cholesterol mg/dl

Fasting triglycerides mg/dl


Concomitant medication

Interval after index event


No. of days to HOMA-IR testing median (IQR)
No. of days to randomization median (IQR)

56 (3098)

56 (3197)

81 (51121)

79 (52121)

* Plusminus values are means SD. There were no significant differences between the groups at baseline. Features are
presented as median values when distributions are highly skewed. To convert the values for cholesterol to millimoles
per liter, multiply by 0.02586. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert
the values for triglycerides to millimoles per liter, multiply by 0.01129. ACE denotes angiotensin-converting enzyme,
HDL high-density lipoprotein, HOMA-IR homeostasis model assessment of insulin resistance, IQR interquartile range,
and LDL low-density lipoprotein.
Race or ethnic group was self-reported.
The body-mass index is the weight in kilograms divided by the square of the height in meters. Scores on the Modified
MiniMental State Examination range from 0 to 100, with higher scores indicating better function. Scores on the
National Institutes of Health (NIH) Stroke Scale range from 0 to 42, with higher scores indicating worse function.
Scores on the Modified Rankin Scale range from 0 to 5, with higher scores indicating worse function.
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Table 2. Primary and Secondary Outcomes.


Pioglitazone
(N=1939)

Outcome

Placebo
(N=1937)

Hazard Ratio
(95% CI)*

Adjusted
P Value

0.76 (0.62 0.93)

0.007

no. of patients (%)


Primary outcome
Stroke or myocardial infarction
Stroke
Fatal
Nonfatal
Myocardial infarction
Fatal

175 (9.0)

228 (11.8)

123 (6.3)

150 (7.7)

9 (0.5)

13 (0.7)

114 (5.9)

137 (7.1)

52 (2.7)

78 (4.0)

7 (0.4)

14 (0.7)

45 (2.3)

64 (3.3)

127 (6.5)

154 (8.0)

0.82 (0.611.10)

0.19

Acute coronary syndrome: myocardial infarction or unstable angina

96 (5.0)

128 (6.6)

0.75 (0.521.07)

0.11

Stroke, myocardial infarction, or serious


heart failure

206 (10.6)

249 (12.9)

0.82 (0.651.05)

0.11

73 (3.8)

149 (7.7)

0.48 (0.330.69)

<0.001

136 (7.0)

146 (7.5)

0.93 (0.731.17)

0.52

Nonfatal
Secondary outcome
Stroke

Diabetes mellitus
Death from any cause

* Hazard ratios were calculated by means of a Cox regression model with corresponding 95% confidence intervals. The
confidence interval for the primary outcome was adjusted for interim monitoring; confidence intervals for the secondary outcomes were adjusted for multiple comparisons.
The P value for the primary outcome was adjusted for interim monitoring. P values for the five secondary outcomes
were adjusted for multiple comparisons by the Hochberg procedure using an overall familywise type I error of 5%.
Only the first event, stroke or myocardial infarction, was counted for each patient.
In the composite categories, only the first event was counted for each patient (e.g., a patient with myocardial infarction
followed by unstable angina would be counted only as having a myocardial infarction in the category for acute coronary
syndrome). More strokes are listed as occurring as a secondary outcome than a primary outcome because the secondary outcome included strokes occurring after myocardial infarction.
Serious heart failure was defined as an episode resulting in hospitalization or death.

P=0.88). There were no significant differences


in any of the prespecified subgroups (Fig. 2).
In ancillary analyses, the effect of pioglita
zone on the primary outcome was similar when
stroke and myocardial infarction were defined
according to updated criteria28,29 (hazard ratio,
0.73; 95% CI, 0.60 to 0.88). The finding for diabetes was also unchanged when a cutoff for
glycated hemoglobin of 6.5% or more was used
in local analysis, consistent with the 2010 ADA
recommendation30 (hazard ratio, 0.49; 95% CI,
0.38 to 0.64).
After 1 year, the HOMA-IR index and C-reactive protein level were lower in the pioglitazone
group than in the placebo group (Table S6 in the
Supplementary Appendix). During the trial, levels
of fasting glucose, fasting triglycerides, and systolic blood pressure were also lower in the pioglitazone group, as was diastolic blood pressure in
years 1 to 4. Levels of both high-density lipopro1326

tein (HDL) cholesterol and low-density lipoprotein


(LDL) cholesterol were higher in the pioglitazone
group than in the placebo group (Fig. S2 in the
Supplementary Appendix).
Safety Outcomes

Patients in the pioglitazone group had more


weight gain, edema, shortness of breath, and
bone fractures than did patients in the placebo
group (Table3, and Table S7 in the Supplementary Appendix). The maximum between-group
difference in weight change was observed at year
4 (mean weight gain of 2.6 kg in the pioglita
zone group vs. mean weight loss of 0.5 kg in the
placebo group, P<0.001). Among the patients in
the pioglitazone group, 52.2% gained more than
4.5 kg and 11.4% gained more than 13.6 kg; the
corresponding percentages in the placebo group
were 33.7% and 4.5%. The rates of edema were
higher in the pioglitazone group than in the

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Pioglitazone after Ischemic Stroke or TIA

Discussion
In this trial involving patients without diabetes
who had a recent history of ischemic stroke or
TIA and who had insulin resistance, the rate of
the primary outcome was lower among patients
who received pioglitazone than among those who
received placebo. The incidence of a new diagnosis of diabetes was also lower with pioglitazone.
The results of the IRIS trial are in contrast to
the findings of two trials involving patients with
type 2 diabetes. In the Prospective Pioglitazone
Clinical Trial in Macrovascular Events (PROactive)
trial,15,16 the rate of primary outcome of death,
myocardial infarction, stroke, acute coronary syndrome, vascular surgery, or amputation was not
significantly lower among patients in the pioglitazone group than among those in the placebo
group. In the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial,31 the
rate of primary outcome of death, stroke, or myocardial infarction was not significantly lower
among patients receiving rosiglitazone and metformin (insulin-sparing strategy) than among
those receiving insulin and sulfonylurea therapy
(insulin-providing strategy). However, the IRIS
results are consistent with findings regarding a
secondary outcome in the PROactive trial (i.e.,

1.00

Cumulative Probability of Event-free


Survival

placebo group (35.6% vs. 24.9%, P<0.001), as were


rates of serious bone fracture (i.e., requiring hospitalization or surgery), which were reported in
99 patients and 62 patients, respectively (5.1% vs.
3.2%, P=0.003).
Although shortness of breath was reported
more frequently in the pioglitazone group than
in the placebo group, there was no significant
between-group difference in the number of patients with heart failure (74 in the pioglitazone
group and 71 in the placebo group, P=0.80) or
in the number of patients hospitalized for heart
failure (51 and 42, respectively; P=0.35) (Table
S7 in the Supplementary Appendix). Incident
bladder cancer occurred in 12 patients in the
pioglitazone group and in 8 in the placebo
group (P=0.37). The total incidence of cancer did
not differ significantly between the two groups
(133 patients and 150 patients, respectively;
P=0.29). There was no significant between-group
difference in the incidence of other monitored
adverse events, with the exception of a change in
the alanine aminotransferase level, which was
more favorable with pioglitazone.

0.90
0.80

1.00

0.70

0.95

0.60

Pioglitazone

0.50

0.90

0.40

0.85

Placebo

0.30
0.80

0.20

0.00

0.10
0.00

Hazard ratio, 0.76 (95% CI, 0.620.93)


P=0.007

1
2

3
3

1196
1182

481
459

Years since Randomization


No. at Risk
Pioglitazone
Placebo

1939
1937

1793
1778

1701
1690

1491
1476

Figure 1. Primary Outcome.


By 5 years, the primary outcome (fatal or nonfatal stroke or fatal or nonfatal
myocardial infarction) had occurred in 175 of 1939 patients (9.0%) in the
pioglitazone group and in 228 of 1937 (11.8%) in the placebo group. The
inset shows the same data on an enlarged y axis. The numbers at risk were
the numbers of patients who were alive without an event and still being followed at the beginning of each time point.

that the rates of death, myocardial infarction, or


stroke were significantly lower with pioglitazone
than with placebo) and with findings of trials
showing a favorable effect of pioglitazone on the
progression of subclinical atherosclerosis among
patients with and those without diabetes.32-34
In our trial, the mechanism that is responsible
for the lower rates of stroke and myocardial
infarction in the pioglitazone group than in the
placebo group is uncertain. Pioglitazone activates PPAR- and also causes partial activation of
PPAR-.35 These actions modulate the transcription of genes with favorable effects on insulin
sensitivity,13,36 fat distribution,37 plasma glucose,35,38
lipid and protein metabolism,36,38 vascular endothelial function,39 and inflammation.35,40 In the
IRIS trial, pioglitazone improved insulin sensitivity, blood pressure, and circulating levels of glucose, triglycerides, HDL cholesterol, and C-reactive
protein. The enhancement of insulin sensitivity
may be central to the benefit of pioglitazone.
However, other measured and unmeasured effects may have contributed to the benefit of the
drug with respect to our primary outcome.
We observed previously recognized adverse effects of pioglitazone on weight gain, edema, and
bone fracture. Weight gain with PPAR- agonists,
such as pioglitazone, reflects an increase in adi-

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1327

The

Subgroup

Pioglitazone

n e w e ng l a n d j o u r na l

Placebo

of

m e dic i n e

P Value for
Interaction

Hazard Ratio (95% CI)

no. of events/total no. (%)


Age
<65 yr
65 yr
Sex
Male
Female
Race
White
Black
Other
Ethnic group
Hispanic
Non-Hispanic
Body-mass index
<30
30
Coronary artery disease
Yes
No
Hypertension
Yes
No
HOMA-IR index
<4.6
4.6
Glycated hemoglobin
<5.7%
5.7%
HDL cholesterol
<40 mg/dl
40 mg/dl
Fasting glucose
<100 mg/dl
100 mg/dl
Triglycerides
<150 mg/dl
150 mg/dl
Medication adherence
<80%
80%

0.72
81/1077 (7.5)
94/862 (10.9)

111/1091 (10.2)
117/846 (13.8)

0.73 (0.550.97)
0.79 (0.601.03)

126/1293 (9.7)
49/646 (7.6)

147/1245 (11.8)
81/692 (11.7)

0.81 (0.641.03)
0.65 (0.460.93)

144/1600 (9.0)
22/218 (10.1)
8/88 (9.1)

189/1619 (11.7)
32/225 (14.2)
5/60 (8.3)

0.77 (0.620.95)
0.67 (0.391.16)
1.08 (0.353.29)

7/75 (9.3)
168/1852 (9.1)

12/72 (16.7)
215/1857 (11.6)

0.58 (0.231.46)
0.78 (0.630.95)

99/1123 (8.8)
75/810 (9.3)

142/1096 (13.0)
85/835 (10.2)

0.67 (0.520.87)
0.91 (0.671.24)

36/241 (14.9)
139/1697 (8.2)

47/221 (21.3)
181/1715 (10.6)

0.70 (0.451.08)
0.77 (0.620.96)

141/1380 (10.2) 186/1390 (13.4)


34/558 (6.1)
42/546 (7.7)

0.76 (0.610.95)
0.77 (0.491.21)

0.30

0.75

0.51

0.14

0.72

0.94

0.25
76/933 (8.1)
99/1006 (9.8)

114/948 (12.0)
114/989 (11.5)

0.67 (0.500.90)
0.85 (0.651.11)

52/672 (7.7)
123/1266 (9.7)

78/690 (11.3)
150/1247 (12.0)

0.67 (0.470.95)
0.81 (0.641.02)

77/787 (9.8)
98/1147 (8.5)

84/785 (10.7)
144/1149 (12.5)

0.90 (0.661.23)
0.68 (0.530.88)

106/1126 (9.4)
69/813 (8.5)

132/1137 (11.6)
96/800 (12.0)

0.81 (0.621.04)
0.70 (0.510.95)

111/1260 (8.8)
64/675 (9.5)

137/1293 (10.6)
91/641 (14.2)

0.83 (0.651.07)
0.65 (0.470.89)

0.38

0.17

0.48

0.22

0.79
0.69 (0.530.89)
0.73 (0.531.00)

111/1071 (10.4) 123/834 (14.7)


61/861 (7.1)
103/1090 (9.4)
0.25

0.50

Pioglitazone Better

1.0

1.5

2.0

3.0

Placebo Better

Figure 2. Subgroup Analyses of the Primary Outcome.


Shown is the relative benefit of pioglitazone as compared with placebo in 13 subgroups that were examined for their interaction with the
treatment. P values have not been adjusted for multiple comparisons. (P=0.94 after adjustment for multiple comparisons in each subgroup.) The size of the squares corresponds to the number of patients in each subgroup. The body-mass index is the weight in kilograms
divided by the square of the height in meters. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert
the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for triglycerides to millimoles per liter, multiply
by 0.01129. HDL denotes high-density lipoprotein, and HOMA-IR homeostasis model assessment of insulin resistance.

pose tissue mass and a tendency for fluid accumulation owing to renal sodium retention.41
Sodium retention, if unchecked, can also increase the risk of heart failure.42 However, in the
IRIS trial, we did not observe a greater incidence
1328

of heart failure in the pioglitazone group than in


the placebo group, which was probably because
we excluded patients with a history of heart failure and used safety algorithms that triggered
dose reduction for excessive weight gain or edema.

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Pioglitazone after Ischemic Stroke or TIA

Table 3. Adverse Events, According to Severity.*


Pioglitazone
(N=1939)

Event

Placebo
(N=1937)

P Value

no. of patients (%)


Serious adverse event
Hospitalization

908 (46.8)

946 (48.8)

0.21

Death

136 (7.0)

146 (7.5)

0.53

133 (6.9)

150 (7.7)

0.29

28 (1.4)

25 (1.3)

0.68

Incident cancer
Any
Prostate
Breast

10 (0.5)

16 (0.8)

0.24

Lung

13 (0.7)

11 (0.6)

0.68

Bladder

12 (0.6)

8 (0.4)

0.37

75 (3.9)

93 (4.8)

0.15

Bone fracture

Other

99 (5.1)

62 (3.2)

0.003

Heart failure

51 (2.6)

42 (2.2)

0.35

2 (0.1)

1 (0.1)

0.50

Other
Other adverse event
Bone fracture

133 (6.9)

94 (4.9)

0.008

Heart failure

29 (1.5)

32 (1.7)

0.70

>4.5 kg

1013 (52.2)

653 (33.7)

<0.001

>13.6 kg

221 (11.4)

88 (4.5)

<0.001
<0.001

Weight gain

Edema

691 (35.6)

483 (24.9)

Shortness of breath

342 (17.6)

292 (15.1)

0.03

26 (1.3)

59 (3.0)

<0.001

3 (0.2)

2 (0.1)

0.66

Alanine aminotransferase >ULN


Macular edema

* ULN denotes the upper limit of the normal range.


This category of adjudicated bone fracture refers to bone fracture that resulted in hospitalization, surgery, or a procedure.
This category of adjudicated heart failure refers to heart failure that resulted in hospitalization or death.
Other serious events included sigmoid lipoma resulting in obstruction and sigmoid colectomy and hypoglycemia with
unresponsiveness in the pioglitazone group and severe headache in the placebo group.
Included in this category are adjudicated events that did not meet the criteria for serious events, as defined above.
Edema was defined as self-reported new or worse swelling of the feet or lower legs.

Pioglitazone has been associated with an increased risk of bone fracture.43 The mechanism
is uncertain, and studies have not shown a consistent effect of the drug on bone density.44,45
Observational research conducted in 2011 and
2012 suggested that pioglitazone may increase
the risk of bladder cancer.46,47 However, more recent studies48,49 showed no significant association
for any dose or duration of therapy.49 Other research suggests that PPAR- agonists might prevent certain cancers.50,51 Although we did not observe a significant effect of treatment on the
incidence of total or any specific cancer, our study
was not powered to address these questions.
The patients in our study were classified as
having insulin resistance on the basis of the

HOMA-IR index. We selected this measurement


because it is easy to perform and is closely correlated with more definitive but complex tests.20,52
However, a component of the HOMA-IR index is
the plasma insulin level, which is not globally
standardized. To account for this, all HOMA-IR
testing in the IRIS trial was performed in central
laboratories. To replicate IRIS eligibility criteria,
laboratories would need either to adopt the IRIS
assays or to calibrate their own results to the
IRIS assays.
In conclusion, we found that pioglitazone, a
therapy directed at improving insulin sensitivity,
can prevent cardiovascular events among patients
who have insulin resistance along with cerebrovascular disease. The findings suggest that the

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1329

The

n e w e ng l a n d j o u r na l

administration of pioglitazone in 100 patients


similar to those in our trial for about 5 years
could prevent 3 patients from having a stroke or
myocardial infarction. However, during the same
period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in 2 patients. It seems reasonable
to consider individual treatment preference and
risk of drug-related adverse events in addition to
potential benefits when making patient-specific
decisions regarding therapy.
Supported by a grant (U01NS044876) from the National Institute of Neurological Disorders and Stroke. Pioglitazone and placebo were provided by Takeda Pharmaceuticals International.
Dr. Young reports receiving grant support through his institution from Merck and Mifcor; Dr. Inzucchi, receiving fees for
serving on advisory boards from Merck, Janssen, Sanofi, Poxel,
Boehringer Ingelheim, Eli Lilly, and AstraZeneca, fees for serving on a data monitoring committee from Novo Nordisk and
Intarcia, and fees for serving on a steering committee from
Lexicon, serving as an expert witness on behalf of Takeda in a
patent litigation deposition, and participating in projects for

of

m e dic i n e

which funding for continuing medical education has been provided to Yale University by Boehringer Ingelheim, Eli Lilly, Novo
Nordisk, Abbott, Merck, and Sanofi; Dr. Peduzzi, receiving
consulting fees from Millennium; Dr. Schwartz, receiving grant
support from Cerenis, Roche, Resverlogix, Sanofi, and the
Medicines Company; Dr. Ford, receiving fees for serving on a
trial steering committee from Lundbeck, fees for serving on a data
safety monitoring board from Cerevast, fees for serving on advisory boards from Pfizer, Athersys, and Daiichi Sankyo, consulting fees from Pfizer, and lecture fees and travel support from
AstraZeneca and Boehringer Ingelheim; Dr. Ringleb, receiving
fees for serving on advisory boards from Boehringer Ingelheim,
Covidien, Bayer, and Daiichi Sankyo and lecture fees and travel
support from Boehringer Ingelheim, Bayer, and Daiichi Sankyo;
Dr. Spence, receiving consulting and lecture fees from Bayer and
Bristol-Myers Squibb, serving as an officer of and having an equity
interest in Vascularis, and performing contract research for
Bayer, Bristol-Myers Squibb, Pfizer, Acasti Pharma, POM Wonderful, CVRx, AGA Medical, and W.L. Gore. No other potential
conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the patients who participated in the IRIS trial and
the study coordinators who implemented the protocol; and Osama
Abdelghany and his staff at the Investigational Drug Service of
YaleNew Haven Hospital, New Haven, Connecticut.

Appendix
The authors full names and academic degrees are as follows: WalterN. Kernan, M.D., CatherineM. Viscoli, Ph.D., KarenL. Furie,
M.D., M.P.H., LawrenceH. Young, M.D., SilvioE. Inzucchi, M.D., Mark Gorman, M.D., PeterD. Guarino, Ph.D., AnneM. Lovejoy,
P.A.-C., PeterN. Peduzzi, Ph.D., Robin Conwit, M.D., LawrenceM. Brass, M.D., GregoryG. Schwartz, M.D., Ph.D., HaroldP. Adams,
Jr., M.D., Leo Berger, M.D., Antonio Carolei, M.D., Wayne Clark, M.D., Bruce Coull, M.D., GaryA. Ford, M.B., B.Chir., Dawn Kleindorfer, M.D., JohnR. OLeary, M.A., MarkW. Parsons, M.D., Peter Ringleb, M.D., Souvik Sen, M.D., J.David Spence, M.D., David
Tanne, M.D., David Wang, M.D., and ToniR. Winder, M.D., for the IRIS Trial Investigators
The authors affiliations are as follows: the School of Medicine (W.N.K., C.M.V., L.H.Y., S.E.I., A.M.L., L.M.B., J.R.O.) and the School
of Public Health (P.D.G., P.N.P., J.R.O.), Yale University, New Haven, and the Cooperative Studies Program Coordinating Center, Veteran Affairs (VA) Connecticut HealthCare System, West Haven (P.D.G., P.N.P.) all in Connecticut; Alpert Medical School, Brown
University, Providence, RI (K.L.F.); Vermont College of Medicine, Burlington (M.G.); the National Institute of Neurological Disorders
and Stroke, Bethesda, MD (R.C.); the VA Medical Center and the University of Colorado School of Medicine, Denver (G.G.S.); the University of Iowa, Iowa City (H.P.A.); Hpital Charles LeMoyne, Greenfield Park, QC (L.B.), the University of Western Ontario, London
(J.D.S.), and the Center for Neurological Research, Lethbridge, AB (T.R.W.) all in Canada; University of LAquila, LAquila, Italy
(A.C.); Oregon Health Sciences University, Portland (W.C.); the University of Arizona, Tucson (B.C.); the University of Oxford and
Oxford University Hospitals NHS Foundation Trust, Oxfordshire, United Kingdom (G.A.F.); the University of Cincinnati, Cincinnati
(D.K.); John Hunter Hospital, University of Newcastle, New Lambton Heights, NSW, Australia (M.W.P.); the University of Heidelberg,
Heidelberg, Germany (P.R.); the University of South Carolina School of Medicine, Columbia (S.S.); Sheba Medical Center, Tel Aviv
University, Tel Aviv, Israel (D.T.); and the Illinois Neurological InstituteOSF Saint Francis Medical Center and the Department of
Neurology, University of Illinois College of Medicine at Peoria, Peoria (D.W.).
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